Cells exposed in culture to a single chemotherapeutic agent often develop a resistance to that drug and frequently these cells also become cross resistant to a range of chemically unrelated compounds. This phenomenon of multidrug resistance is associated with increased expression of a membrane protein, p-glycoprotein, which is the product of the mdrl gene. Similarly, chemically induced rat hepatomas are frequently observed to be resistant to the cytotoxic and growth inhibitory actions of the carcinogens. The role of the mdr gene(s) in hepatocarcinogenesis is yet unknown. We have previously observed increased steady state levels of mdr mRNA in the livers of rats exposed to carcinogens such as Aflatoxin B1, TCDD, AAF and isosafrole. These compounds also increased the expression of members of the cytochrome p4501A class. The objectives of this project are as follows: 1) to investigate the mechanisms which regulate the rat mdr gene(s) in response to exposure to xenobiotic agents, 2) to study possible co-regulation of the mdr gene(s) with cytochrome p450 genes and define the mechanisms by which this co-regulation occurs, and 3) to clone and characterize members of the rat mdr gene family.